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. 2015 Jun 3;56(23):3354-3457.
doi: 10.1016/j.tetlet.2015.02.062.

Scalable syntheses of the BET bromodomain inhibitor JQ1

Shameem Sultana Syeda  1 , Sudhakar Jakkaraj  1 , Gunda I Georg  1
Affiliations

Scalable syntheses of the BET bromodomain inhibitor JQ1

Shameem Sultana Syeda et al. Tetrahedron Lett. .

Abstract

We have developed methods involving the use of alternate, safer reagents for the scalable syntheses of the potent BET bromodomain inhibitor JQ1. A one-pot three step method, involving the conversion of a benzodiazepine to a thioamde using Lawesson's reagent, followed by amidrazone formation and installation of the triazole moiety furnished JQ1. This method provides good yields and a facile purification process. For the synthesis of enantiomerically enriched (+)-JQ1, the highly toxic reagent diethyl chlorophosphate, used in a previous synthesis, was replaced with the safer reagent diphenyl chlorophosphate in the three-step one-pot triazole formation without effecting yields and enantiomeric purity of (+)-JQ1.

Keywords: BET inhibitors; Bromodomains; Male contraceptive; One-pot method; Thionation; Triazolothienodiazepine (+)-JQ1.

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Figures

Figure 1
Figure 1
Structures of BET inhibitors
Scheme 1
Scheme 1
Filippakopoulos et al. method for the synthesis of (±)-JQ1
Scheme 2
Scheme 2
Filippakopoulos et al. method for the synthesis of enantiomerically enriched (+)-JQ1
Scheme 3
Scheme 3
Thionation of amide 5 with Lawesson’s reagent
Scheme 4
Scheme 4
Synthesis of (±)-JQ1 via a one-pot method
Scheme 5
Scheme 5
Synthesis of enantiomerically enriched (+)-JQ1 with diphenyl chlorophosphate
See this image and copyright information in PMC

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